Trithorax-like group complex containing KDM6A acts antagonistically to Polycomb-repressive complex 2 (PRC2) containing EZH2 in maintaining the dynamics of the repression and activation of gene expression through H3K27 methylation. In urothelial bladder carcinoma, (a H3K27 demethylase) is frequently mutated, but its functional consequences and therapeutic targetability remain unknown. About 70% of mutations resulted in a total loss of expression and a consequent loss of demethylase function in this cancer type. Further transcriptome analysis found multiple deregulated pathways, especially PRC2/EZH2, in -mutated urothelial bladder carcinoma. Chromatin immunoprecipitation sequencing analysis revealed enrichment of H3K27me3 at specific loci in-null cells, including PRC2/EZH2 and their downstream targets. Consequently, we targeted EZH2 (an H3K27 methylase) and demonstrated that -null urothelial bladder carcinoma cell lines were sensitive to EZH2 inhibition. Loss- and gain-of-function assays confirmed that cells with loss of KDM6A are vulnerable to EZH2. IGFBP3, a direct KDM6A/EZH2/H3K27me3 target, was up-regulated by EZH2 inhibition and contributed to the observed EZH2-dependent growth suppression in-null cell lines. EZH2 inhibition delayed tumor onset in -null cells and caused regression of-null bladder tumors in both patient-derived and cell line xenograft models. In summary, our study demonstrates that inactivating mutations of , which are common in urothelial bladder carcinoma, are potentially targetable by inhibiting EZH2.

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ObjectiveTo review the surgical and clinical results of minimally invasive resection of intrathoracic neurogenic tumors using a videoassisted thoracoscopic technique. Summary Background DataThoracoscopy has emerged as a possible means for diagnosing and managing various intrathoracic disorders. Benign intrathoracic tumors often are ideal lesions for resection using a video-assisted technique. The authors report on their combined experience with the thoracoscopic resection of 143 intrathoracic neurogenic tumors. MethodsBetween March 1992 and February 1999, 143 patients with intrathoracic neurogenic tumors were diagnosed and underwent resection using video-assisted thoracoscopic techniques in three teaching centers. Case selection, surgical technique, and clinical results were reviewed. ResultsThe average age of the patients was 40.8 years; 57.3% were male. Thirty-eight patients (27%) had symptoms attributable to the masses. Seventy-two masses were neurofibromas, 33 were neurilemmomas, 7 were paragangliomas, and 31 were ganglioneuromas. All but seven tumors were located in the posterior mediastinum. The masses were on average 3.5 cm in greatest diameter. The mean surgical time was 40 minutes, and the average hospital stay was 4.1 days. There were no major postoperative complications or recurrences to date. Nine patients reported paresthesias over the chest wall during a mean follow-up of 29 months. ConclusionsResection of intrathoracic neurogenic tumors using a thoracoscopic technique based on standard surgical indications would seem to be appropriate. Most of these masses are benign and readily removed. For dumbbell tumors, a combined thoracic and neurosurgical approach is mandatory.Intrathoracic neurogenic tumors are neoplasms that arise from any of the neural elements in the thorax. These tumors are derived from the various neural elements (nerve sheath, ganglion, or neurite) of the peripheral, autonomic, or paraganglionic nervous systems. Nerves and ganglia of both the somatic and autonomic nervous systems are found throughout the thorax but are concentrated in the paravertebral sulcus region, commonly designated as the posterior mediastinum. Intercostal nerve rami and the sympathetic chain found in this region account for 95% of intrathoracic neurogenic tumors.1 Before the advent of video-thoracoscopy, most nerve sheath and autonomic system tumors were best approached by a standard posterolateral thoracotomy. 2-6More recently, attempts have been made to resect these tumors thoracoscopically in a minimally invasive manner. [7][8][9] Given the advantages shown by the efficacy of these techniques and their less invasive nature, we have chosen video-thoracoscopy as the procedure of choice to remove intrathoracic neurogenic tumors in recent years. This report reviews our combined experiences and clinical results.

Enterovirus 71 (EV71) has emerged as an important virulent neurotropic enterovirus in young children. DTriP-22 (4{4-[(2-bromo-phenyl)-(3-methyl-thiophen-2-yl)-methyl]-piperazin-1-yl}-1-pheny-1H-pyrazolo[3,4-d]pyrimidine)was found to be a novel and potent inhibitor of EV71. The molecular target of this compound was identified by analyzing DTriP-22-resistant viruses. A substitution of lysine for Arg163 in EV71 3D polymerase rendered the virus drug resistant. DTriP-22 exhibited the ability to inhibit viral replication by reducing viral RNA accumulation. The compound suppressed the accumulated levels of both positive-and negative-stranded viral RNA during virus infection. An in vitro polymerase assay indicated that DTriP-22 inhibited the poly(U) elongation activity, but not the VPg uridylylation activity, of EV71 polymerase. These findings demonstrate that the nonnucleoside analogue DTriP-22 acts as a novel inhibitor of EV71 polymerase. DTriP-22 also exhibited a broad spectrum of antiviral activity against other picornaviruses, which highlights its potential in the development of antiviral agents.Enterovirus 71 (EV71), a positive-stranded RNA virus, belongs to the genus Enterovirus in the family Picornaviridae. EV71 infection typically causes hand, foot, and mouth disease or herpangina, followed by severe central nervous system complications, including aseptic meningitis, encephalitis, poliomyelitis-like paralysis, neurogenic cardiopulmonary failure, and even death in some young children. Infants, following infection by EV71 with central nervous system complications, reportedly suffer from neurologic sequelae and delayed neurodevelopment (6). In 1998, a large outbreak of EV71 infection occurred in Taiwan, resulting in almost 80 fatalities and 405 severe cases (7, 21). Subsequently, many outbreaks of EV71 infection in Taiwan have been reported, with a total of 51 verified fatal cases in 2000 and 2001 (29). Severe EV71 infections continued to occur for several years thereafter. EV71 infection also has been reported to occur in many countries, such as Malaysia, Singapore, Australia, Japan, the United States, Germany, and mainland China (1-3, 5, 13, 22, 33, 34).The development of anti-EV71 agents is important because EV71 is regarded as the most important neurotropic enterovirus, after poliovirus control (34). A novel series of pyridyl imidazolidinones targeting VP1 protein, based on the skeletons of WIN compounds, has been developed using computerassisted drug design (37). The new EV71 3C protease inhibitors, based on rhinovirus 3C protease inhibitor AG7088, exhibit inhibitory activities in both enzymatic and cell-based assays (25). A pharmacologically active drug library has been employed to identify anti-EV71 compounds (4). Ribavirin used in combination with interferon to treat patients with hepatitis C virus infection reduces the mortality rate of EV71-infected mice by reducing viral replication (26).We previously discovered piperazine-containing pyrazolo [3,4-d]pyrimidine derivatives as a novel class of anti-EV71 c...

BACKGROUND:The identification of potential tumor markers will help improve therapeutic planning and patient management. Therefore, the aim of this study was to highlight the role of DNA methyltransferase 1 (DNMT1) in bladder cancer. METHODS: A total of 50 samples of nonmalignant urothelium, 65 of muscle-invasive bladder cancers, 15 of distant metastasis, and 50 of nonmuscle-invasive bladder cancers were selected for immunohistochemical staining analysis. Furthermore, human bladder cancer cell lines HT1376 and HT1197 were selected for cell and animal experiments investigating changes in tumor behavior, treatment response, and related signaling in bladder cancer. RESULTS: The incidence of nuclear DNMT1 immunoreactivity in the bladder cancer specimens (45%) was significantly higher than in nonmalignant urothelium (15%, P ¼ .0005), and the incidence in cancer was positively linked to clinical stage (24% in T1 vs 55% in T2-T4, P ¼ .0007). The staining of DNMT1 was also significantly linked to lower complete response rates (P ¼ .0014) and reduced survival rates (P ¼ .000). By in vitro and in vivo experiments, DNMT1 silencing vector reduced tumor growth and attenuated treatment resistance in bladder cancer cells. Less epithelial-mesenchymal transition, less invasion, and slower tumor growth were noted in cancer cells with inhibited DNMT1. Furthermore, the epidermal growth factor receptor-mediated phosphatidylinositol 3 0 -kinase-protein kinase B pathway might be

Spontaneous pneumothorax in apparently healthy individuals is a relatively common occurrence. The management of patients with spontaneous pneumothorax remains controversial. With the advances in thoracoscopic techniques and instrumentation, video-assisted thoracic surgery (VATS) is now accepted by many as the procedure of choice for surgical treatment of spontaneous pneumothorax. We report our combined experience with 757 patients who suffered from recurrent or persistent spontaneous pneumothorax treated by VATS over a 5-year period. Surgical indications included persistent air leak (n = 165), recurrence (n = 325), radiologically demonstrated huge bulla (n = 12), spontaneous hemopneumothorax (n = 13), incomplete expansion of the lung (n = 212), and bilateral involvement (n = 30). Several surgical procedures were undertaken, based on the thoracoscopic findings: endoscopic stapled bullectomy (n = 312), argon beam coagulation (n = 6), endoscopic suturing (n = 52), and endoloop ligation (n = 352). In 49 cases, mechanical or chemical pleurodesis was the only procedure performed. There were no mortalities or intraoperative hazards. Complications consisted of wound infections (n = 16), localized empyema (n = 2), chest wall bleeding (n = 1), and persistent air leaks (bulla type III) (n = 31). The median duration of the operation was 55 minutes (15-160 minutes), and the average postoperative hospital stay was 4.5 days (range 0-27 days). There were 16 recurrences (2.1%), after a mean follow-up of 30 months (range 1-60 months). Seven patients had recurrence from 9 to 17 months after stapled bullectomy. All the remaining patients had recurrence after failed pleurodesis. On the basis of our results, we conclude that video-assisted thoracoscopic management allows effective, safe performance of standard surgical procedures, avoiding a formal thoracotomy incision. We consider thoracoscopy the treatment of choice for patients with pneumothorax requiring surgical therapy.